Potential treatment target for congenital heart disease identified

WASHINGTON - Two separate but related studies have shown that two drugs - one already approved as an immunosuppressant and the other being tested as an anti-cancer agent - could prevent and reverse hypertrophic cardiomyopathy (HCM) in mouse models of congenital heart disease.

HCM is a condition in which the heart muscle becomes thick, leading to the sudden death in children and young adults.

Researchers at the University Health Network (UHN), Toronto, and Beth Israel Deaconess Medical Centre (BIDMC), Boston, conducted both the studies, co-led by UHN’s Benjamin Neel.

“By studying two of the most commonly mutated pathways in cancer, discerning the mechanism by which they cause congenital disease, and treating two of these disorders with different drugs, we have identified potential therapeutic targets for human disease,” said Neel.

“This is what personalized medicine is all about: understanding in detail how different mutations cause disease, and then targeting these mutations appropriately to tailor individualized treatment,” he said.

“These findings exemplify the importance of basic biological research and collaboration across areas of specialization. In this instance, collaboration showed how understanding cancer can lead to unexpected insights into congenital heart disease, and vice versa,” he added.

The researchers were investigating how a cluster of congenital diseases known as ‘RASopathies’, - defects caused by mutations in different genes in the so-called ‘RAS pathway’, develop.

They focused on two genetic disorders - Noonan Syndrome, which occurs in 1 in 1,000-2,500 live births and causes short stature, facial, blood and cardiovascular abnormalities and the much less common LEOPARD Syndrome, which features short stature, as well as skin, facial, skeletal and cardiovascular abnormalities. HCM is prevalent in both syndromes.

The UHN study team investigated Noonan Syndrome while the Boston team investigated LEOPARD Syndrome.

The researchers introduced the genetic mutations that cause these syndromes into special strains of mice, and were able to reproduce the features of the human disorders.

The Toronto group found that ‘excessive activity of an enzyme called ERK, a downstream target of the RAS pathway, caused HCM in Noonan Syndrome, and successfully used a drug that lowers the activity of this enzyme to decrease pathway activity and normalize all of the features of Noonan Syndrome’, said Neel.

The Boston group found that LEOPARD Syndrome results from excessive activity of a different enzyme downstream of RAS, called mTOR.

Using the mTOR inhibitor Rapamycin, which is already approved as an immunosuppressant, they were able to reverse HCM in their mouse model of LEOPARD Syndrome.

“These research findings are important steps towards understanding the pathogenesis of these congenital syndromes, and point the way toward clinical trials of these agents in severely affected patients,” said Neel.

The findings have been published online ahead of the March issue of the Journal of Clinical Investigation. (ANI)